Han in U.S. Pat. Nos. 5,037,819, 5,110,812, 5,175,283, 5,250,677 and 5,326,863 discloses 3-guanidinoalkyl-2-azetidinones of the formula: 
wherein:
U and W are independently selected from hydrogen and amino protecting groups;
n is an integer from 1 to 3;
X is hydrogen, trialkylsilyl, arylsulfonyl, amino substituted arylsulfonyl, alkylsulfonyl, arylaminocarbonyl, alkylcarbonyl or arylcarbonyl;
Y is hydrogen, arylalkenyl, arylalkyl, formyl, carboxy, alkoxycarbonyl, acyloxy, arylthio, arylsulfinyl, arylsulfonyl, alkythio, alkylsulfinyl, alkylsulfonyl, arylaminocarbonyl, 
xe2x80x83R is hydrogen, alkyl, or arylalkyl;
m is an integer from 1 to 3; and
Rxe2x80x2, is hydrogen or xe2x80x94CO2Rxe2x80x3 wherein Rxe2x80x3 is hydrogen, alkyl, or arylalkyl.
Han further discloses that the above compounds wherein:
U and W are hydrogen;
X is arylsulfonyl, amino substituted arylsulfonyl, alkylsulfonyl, arylaminocarbonyl, alkylcarbonyl, or arylcarbonyl; and
Y is hydrogen, arylalkyl, carboxy, alkoxycarbonyl, acyloxy, arylsulfonyl, alkylthio, alkylsulfonyl, arylaminocarbonyl, 
xe2x80x83R is hydrogen, alkyl or arylalkyl;
Rxe2x80x2, is hydrogen or xe2x80x94CO2Rxe2x80x3;
Rxe2x80x3, is hydrogen, alkyl, or arylalkyl and pharmaceutically acceptable salts thereof are inhibitors against serine proteases, particularly against thrombin and trypsin, and can be used to control blood coagulation or to treat pancreatitis.
Han defines xe2x80x9carylxe2x80x9d as a phenyl or naphthyl group which may be unsubstituted or substituted with one or more groups such as amino, nitro, or alkyl and defines xe2x80x9caminoxe2x80x9d as unsubstituted or substituted with one or two alkyl radicals.
This invention is directed to the novel beta lactam compounds of formulas I, II, III, IV, and V shown below and to the use of such compounds as inhibitors of various in vivo enzyme systems including tryptase, thrombin, trypsin, Factor Xa, Factor VIIa, and urokinase-type plasminogen activator. This invention is also directed to the use of the compounds of formula VI shown below as tryptase, Factor Xa, Factor VIIa, and urokinase-type plasminogen activator inhibitors.
Compounds of this invention include the formula: 
wherein:
R1 is hydrogen, carboxy, alkoxycarbonyl, A2-aryl, 
or R1 is alkyl provided that R2 is alkyl and R3 is hydrogen.
R2 and R3 are both hydrogen, or R2 is alkyl provided that R3 is hydrogen, or R3 is alkyl provided that R2 is hydrogen. 
R4 and R5 are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, A2-cycloalkyl, A2-substituted cycloalkyl, aryl, substituted aryl, A2-aryl, A2-substituted aryl, heteroaryl, A2-heteroaryl, heterocycloalkyl, A2-heterocycloalkyl, aryl-A3-aryl, A2-aryl-A3-aryl, aryl-A3-cycloalkyl, A2-aryl-A3-cycloalkyl, aryl-A3-heteroaryl, A2-aryl-A3-heteroaryl, aryl-A3-heterocycloalkyl, A2-aryl-A3-heterocycloalkyl, aryl-A3-substituted aryl, A2-aryl-A3-substitued aryl, aryl-A3-substituted cycloalkyl, A2-aryl-A3-substituted cycloalkyl, cycloalkyl-A3-cycloalkyl, A2-cycloalkyl-A3-cycloalkyl, cycloalkyl-A3-aryl, A2-cycloalkyl-A3-aryl, cycloalkyl-A3-heteroaryl, A2-cycloalkyl-A3-heteroaryl, cycloalkyl-A3-heterocycloalkyl, A2-cycloalkyl-A3-heterocycloalkyl, cycloalkyl-A3-substituted cycloalkyl, A2-cycloalkyl-A3-substituted cycloalkyl, cycloalkyl-A3-substituted aryl, A2-cycloalkyl-A3-substituted aryl, substituted cycloalkyl-A3-cycloalkyl, A2-substituted cycloalkyl-A3-cycloalkyl, substituted cycloalkyl-A3-substituted cycloalkyl, A2-substituted cycloalkyl-A3-substituted cycloalkyl, substituted cycloalkyl-A3-aryl, A2-substituted cycloalkyl-A3-aryl, substituted cycloalkyl-A3-heteroaryl, A2-substituted cycloalkyl-A3-heteroaryl, substituted cycloalkyl-A3-heterocycloalkyl, A2-substituted cycloalkyl-A3-heterocycloalkyl, substituted cycloalkyl-A3-substituted aryl, A2-substituted cycloalkyl-A3-substituted aryl, heteroaryl-A3-heteroaryl, A2-heteroaryl-A3-heteroaryl, heteroaryl-A3-cycloalkyl, A2-heteroaryl-A3-cycloalkyl, heteroaryl-A3-substituted cycloalkyl, A2-heteroaryl-A3-substituted cycloalkyl, heteroaryl-A3-aryl, A2-heteroaryl-A3-aryl, heteroaryl-A3-heterocycloalkyl, A2-heteroaryl-A3-heterocycloalkyl, heteroaryl-A3-substituted aryl, A2-heteroaryl-A3-substituted aryl, heterocycloalkyl-A3-heterocycloalkyl, A2-heterocycloalkyl-A3-heterocycloalkyl, heterocycloalkyl-A3-cycloalkyl, A2-heterocycloalkyl-A3-cycloalkyl, heterocycloalkyl-A3-substituted cycloalkyl, A2-heterocycloalkyl-A3-substituted cycloalkyl, heterocycloalkyl-A3-aryl, A2-heterocycloalkyl-A3-aryl, heterocycloalkyl-A3-substituted aryl, A2-heterocycloalkyl-A3-substituted aryl, heterocycloalkyl-A3-heteroaryl, A2-heterocycloalkyl-A3-heteroaryl, substituted aryl-A3-substituted aryl, A2-substituted aryl-A3-substituted aryl, substituted aryl-A3-cycloalkyl, A2-substituted aryl-A3-cycloalkyl, substituted aryl-A3-substituted cycloalkyl, A2-substituted aryl-A3-substituted cycloalkyl, substituted aryl-A3-aryl, A2-substituted aryl-A3-aryl, substituted aryl-A3-heteroaryl, A2-substituted aryl-A3-heteroaryl, substituted aryl-A3-heterocycloalkyl, and A2-substituted aryl-A3-heterocycloalkyl.
R6 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, A2-cycloalkyl, A2-substituted cycloalkyl, aryl, substituted aryl, A2-aryl, A2-substituted aryl, aryl-A3-aryl, A2-aryl-A3-aryl, heteroaryl, A2-heteroaryl, heterocycloalkyl, A2-heterocycloalkyl, aryl-A3-cycloalkyl, A2-aryl-A3-cycloalkyl, aryl-A3-heteroaryl, A2-aryl-A3-heteroaryl, aryl-A3-heterocycloalkyl, A2-aryl-A3-heterocycloalkyl, carboxy, alkoxycarbonyl, 
alkoxycarbonylamino, aryloxycarbonylamino, arylcarbonylamino, xe2x80x94N(alkyl)(alkoxycarbonyl), xe2x80x94N(alkyl)(aryloxycarbonyl), alkylcarbonylamino, xe2x80x94N(alkyl)(alkylcarbonyl), or xe2x80x94N(alkyl)(arylcarbonyl).
m is an integer from 1 to 5.
Y is O, S, Nxe2x80x94R4, Nxe2x80x94SO2xe2x80x94R7, 
R7 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, A2-cycloalkyl, A2-substituted cycloalkyl, aryl, substituted aryl, A2-aryl, A2-substituted aryl, heteroaryl, A2-heteroaryl, heterocycloalkyl, A2-heterocycloalkyl, aryl-A3-aryl, A2-aryl-A3-aryl, aryl-A3-cycloalkyl, A2-aryl-A3-cycloalkyl, aryl-A3-heteroaryl, A2-aryl-A3-heteroaryl, aryl-A3-heterocycloalkyl, A2-aryl-A3-heterocycloalkyl, aryl-A3-substituted aryl, A2-aryl-A3-substitued aryl, aryl-A3-substituted cycloalkyl, A2-aryl-A3-substituted cycloalkyl, cycloalkyl-A3-cycloalkyl, A2-cycloalkyl-A3-cycloalkyl, cycloalkyl-A3-aryl, A2-cycloalkyl-A3-aryl, cycloalkyl-A3-heteroaryl, A2-cycloalkyl-A3-heteroaryl, cycloalkyl-A3-heterocycloalkyl, A2-cycloalkyl-A3-heterocycloalkyl, cycloalkyl-A3-substituted cycloalkyl, A2-cycloalkyl-A3-substituted cycloalkyl, cycloalkyl-A3-substituted aryl, A2-cycloalkyl-A3-substituted aryl, substituted cycloalkyl-A3-cycloalkyl, A2-substituted cycloalkyl-A3-cycloalkyl, substituted cycloalkyl-A3-substituted cycloalkyl, A2-substituted cycloalkyl-A3-substituted cycloalkyl, substituted cycloalkyl-A3-aryl, A2-substituted cycloalkyl-A3-aryl, substituted cycloalkyl-A3-heteroaryl, A2-substituted cycloalkyl-A3-heteroaryl, substituted cycloalkyl-A3-heterocycloalkyl, A2-substituted cycloalkyl-A3-heterocycloalkyl, substituted cycloalkyl-A3-substituted aryl, A2-substituted cycloalkyl-A3-substituted aryl, heteroaryl-A3-heteroaryl, A2-heteroaryl-A3-heteroaryl, heteroaryl-A3-cycloalkyl, A2-heteroaryl-A3-cycloalkyl, heteroaryl-A3-substituted cycloalkyl, A2-heteroaryl-A3-substituted cycloalkyl, heteroaryl-A3-aryl, A2-heteroaryl-A3-aryl, heteroaryl-A3-heterocycloalkyl, A2-heteroaryl-A3-heterocycloalkyl, heteroaryl-A3-substituted aryl, A2-heteroaryl-A3-substituted aryl, heterocycloalkyl-A3-heterocycloalkyl, A2-heterocycloalkyl-A3-heterocycloalkyl, heterocycloalkyl-A3-cycloalkyl, A2-heterocycloalkyl-A3-cycloalkyl, heterocycloalkyl-A3-substituted cycloalkyl, A2-heterocycloalkyl-A3-substituted cycloalkyl, heterocycloalkyl-A3-aryl, A2-heterocycloalkyl-A3-aryl, heterocycloalkyl-A3-substituted aryl, A2-heterocycloalkyl-A3-substituted aryl, heterocycloalkyl-A3-heteroaryl, A2-heterocycloalkyl-A3-heteroaryl, substituted aryl-A3-substituted aryl, A2-substituted aryl-A3-substituted aryl, substituted aryl-A3-cycloalkyl, A2-substituted aryl-A3-cycloalkyl, substituted aryl-A3-substituted cycloalkyl, A2-substituted aryl-A3-substituted cycloalkyl, substituted aryl-A3-aryl, A2-substituted aryl-A3-aryl, substituted aryl-A3-heteroaryl, A2-substituted aryl-A3-heteroaryl, substituted aryl-A3-heterocycloalkyl, A2-substituted aryl-A3-heterocycloalkyl, 
n and o are one or two provided that the sum of n plus o is two or three.
v and w are one, two, or three provided that the sum of v plus w is three, four, or five.
R8 is hydrogen, halo, amino, xe2x80x94NH(lower alkyl), xe2x80x94N(lower alkyl)2, nitro, alkyl, substituted alkyl, alkoxy, hydroxy, aryl, substituted aryl, A2-aryl, A2-substituted aryl, aryl-A3-aryl, A2-aryl-A3-aryl, cycloalkyl, substituted cycloalkyl, A2-cycloalkyl, A2-substituted cycloalkyl, heteroaryl, A2-heteroaryl, heterocycloalkyl, A2-heterocycloalkyl, aryl-A3-cycloalkyl, A2-aryl-A3-cycloalkyl, aryl-A3-heteroaryl, A2-aryl-A3-heteroaryl, aryl-A3-heterocycloalkyl, or A2-aryl-A3-heterocycloalkyl.
B1, B2 and B3 are each CH, or two of B1, B2 and B3 are CH and the other is N, or one of B1, B2 and B3 is CH and the other two are N.
R9 is hydrogen or lower alkyl.
R10 is alkyl, substituted alkyl, alkyl-O-alkyl, alkyl-O-alkyl-O-alkyl, cycloalkyl, substituted cycloalkyl, A2-cycloalkyl, A2-substituted cycloalkyl, aryl, substituted aryl, A2-aryl, A2-substituted aryl, aryl-A3-aryl, A2-aryl-A3-aryl, heteroaryl, A2-heteroaryl, heterocycloalkyl, A2-heterocycloalkyl, aryl-A3-cycloalkyl, A2-aryl-A3-cycloalkyl, aryl-A3-heteroaryl, A2-aryl-A3-heteroaryl, aryl-A3-heterocycloalkyl or A2-aryl-A3-heterocyloalkyl.
R20 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, A2-cycloalkyl, A2-substituted cycloalkyl, A2-aryl, or A2-substituted aryl.
R21 and R22 are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, A2-cycloalkyl, A2-substituted cycloalkyl, A2-aryl, and A2-substituted aryl.
p is an integer from 2 to 6.
q is an integer from 1 to 6.
r is zero, one or two.
s is one or two.
t is one, two, three or four.
u is one, two or three.
A2 is an alkylene or a substituted alkylene bridge of 1 to 10 carbons, an alkenyl or substituted alkenyl bridge of 2 to 10 carbons having one or more double bonds, or an alkynyl or substituted alkynyl bridge of 2 to 10 carbons having one or more triple bonds.
A3 is a bond, an alkylene or a substituted alkylene bridge of 1 to 10 carbons, an alkenyl or substituted alkenyl bridge of 2 to 10 carbons having one or more double bonds, an alkynyl or substituted alkynyl bridge of 2 to 10 carbons having one or more triple bonds, 
d and e are independently selected from zero and an integer from 1 to 10 provided that the sum of d plus e is no greater than 10.
Compounds of this invention include the formula: 
wherein:
R11 is alkyl.
R1, X1 and q are as defined above.
Compounds of this invention include the formula: 
wherein:
R12 is alkyl.
R1, X1, and q are as defined above.
Compounds of this invention include the formula: 
wherein:
R1 and q are as defined above. 
xe2x80x83provided that 
xe2x80x83is other than alkylcarbonyl, phenylcarbonyl, substituted phenylcarbonyl, naphthylcarbonyl, substituted naphthylcarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, napththylaminocarbonyl, or substituted naphthylaminocarbonyl, or xe2x80x94SO2xe2x80x94R7 provided that xe2x80x94SO2R7 is other than alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, naphthylsulfonyl or substituted naphthylsulfonyl.
R4, R5, Y, R6, m, n, o, B1, B2, B3, R8, R9 and R10 are as defined above.
Compounds of this invention include the formula: 
wherein:
f is an integer from 3 to 5. 
xe2x80x83provided that 
xe2x80x83is other than phenylaminocarbonyl, substituted phenylaminocarbonyl, naphthylaminocarbonyl, substituted naphthylaminocarbonyl, carboxymethylaminocarbonyl, or alkoxycarbonylmethylaminocarbonyl, xe2x80x94SO2xe2x80x94R7 provided that xe2x80x94SO2R7 is other than alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, naphthylsulfonyl or substituted naphthylsulfonyl, or 
provided that if m is 1, 2 or 3 than R6 is other than hydrogen, carboxy, alkoxycarbonyl or aryloxycarbonyl.
X3 is phenylaminocarbonyl, substituted phenylaminocarbonyl, naphthylaminocarbonyl, substituted naphthylaminocarbonyl, alkylcarbonyl, phenylcarbonyl, substituted phenylcarbonyl, naphthylcarbonyl, substituted naphthylcarbonyl, alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, naphthylsulfonyl, or substituted naphthylsulfonyl.
R4, R5, Y, m, n, o, B1, B2, B3, v, w, and R8 are as defined above.
This invention is also directed to the use of the beta lactam compounds of formula VI shown below as inhibitors of tryptase, Factor Xa, Factor VIla, and urokinase plaminogen activator. 
wherein:
R14 is hydrogen, carboxy, alkoxycarbonyl, alkylcarbonyl, phenylcarbonyl, substituted phenylcarbonyl, naphthylcarbonyl, substituted naphthylcarbonyl, alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, naphthylsulfonyl, substituted naphthylsulfonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, naphthylaminocarbonyl, substituted naphthylaminocarbonyl, A2-aryl, 
xe2x80x83wherein m is 1, 2 or 3 and R6 is hydrogen, carboxy, alkoxycarbonyl, or aryloxycarbonyl.
X3 and f are as defined above.
The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain radicals having up to ten carbon atoms The term xe2x80x9clower alkylxe2x80x9d refers to straight or branched radicals having up to four carbon atoms and is a preferred subgrouping for the term alkyl.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to such straight or branched chain radicals of 1 to 10 carbons wherein one or more, preferably one, two or three, hydrogens have been replaced by a hydroxy, amino, cyano, halo, trifluoromethyl, nitro, xe2x80x94NH(lower alkyl), xe2x80x94N(lower alkyl)2, alkoxy, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, or alkoxycarbonylamino.
The term xe2x80x9calkoxyxe2x80x9d refers to such alkyl groups as defined above attached to an oxygen. The term xe2x80x9calkylthioxe2x80x9d refers to such alkyl groups as defined above attached to a sulfur. The terms xe2x80x9clower alkoxyxe2x80x9d and xe2x80x9clower alkylthioxe2x80x9d refer to such lower alkyl groups as defined above attached to an oxygen or sulfur.
The term xe2x80x9ccycloalkylxe2x80x9d refers to fully or partially saturated rings of 3 to 7 carbons.
The term xe2x80x9csubstituted cycloalkylxe2x80x9d refers to such rings of 3 to 7 carbons having one or more substituents selected from lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, trifluoromethyl, nitro, cyano, amino, xe2x80x94NH(lower alkyl), xe2x80x94N(lower alkyl)2, or carboxy as well as such rings fused to a phenyl ring such as tetrahydronaphthyl.
The term xe2x80x9carylxe2x80x9d refers to phenyl, 1-naphthyl and 2-naphthyl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to phenyl, 1-naphthyl, and 2-naphthyl having a substituent selected from alkyl of 1 to 10 carbons, lower alkoxy, lower alkylthio, halo, hydroxy, trifluoromethyl, nitro, amino, xe2x80x94NH(loweralkyl), xe2x80x94N(lower alkyl)2, or carboxy, and di and tri-substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halo, hydroxy and amino.
The term xe2x80x9cheteroarylxe2x80x9d refers to unsaturated and partially saturated rings of 4 to 7 atoms containing one or two O and S atoms and/or one to four N atoms, one to three N atoms when the ring is 4 atoms, provided that the total number of hetero atoms in the ring is 4 or less, 3 or less when the ring is 4 atoms. The heteroaryl ring is attached by way of an available carbon or nitrogen atom. Preferred heteroaryl groups include 2-, 3-, or 4-pyridyl, 4-imidazolyl, 4-thiazolyl, 2- and 3-thienyl, 2- and 3-furyl, and 2-(1,4,5,6-tetrahydropyrimidinyl). The term heteroaryl also includes bicyclic rings wherein the 4 to 7 membered ring containing O, S and N atoms as defined above is fused to a benzene, cycloalkyl, heteroaryl or heterocycloalkyl ring. Preferred bicyclic rings are 2- and 3-indolyl and 4-and 5-quinolinyl. The mono or bicyclic heteroaryl ring can also be additionally substituted at one or more available carbon atoms by a lower alkyl, halo, carboxy, hydroxy, A2-lower alkoxy, A2-guanido, benzyl or cyclohexylmethyl. Also, if the mono or bicyclic ring has an available N-atom such N atom can also be substituted by an N-protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, benzyl or benzhydryl.
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to fully saturated rings of 4 to 7 atoms containing one or two O and S atoms and/or one to four N atoms, one to three N atoms when the ring is 4 atoms, provided that the total number of hetero atoms in the ring is 4 or less, 3 or less when the ring is 4 atoms. The heterocycloalkyl is attached by way of an available carbon or nitrogen atom. Preferred heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, tetrahydro-1,2-thiazinyl, piperazinyl, piperidinyl, homopiperizinyl and azetidinyl. The term heterocycloalkyl also includes bicyclic rings wherein the 4 to 7 membered saturated ring containing O, S and N atoms as defined above is fused to a cycloalkyl, benzene, heteroaryl, or heterocycloalkyl ring. The mono or bicyclic heterocycloalkyl ring can also be substituted at one or more available carbon atoms by a lower alkyl, halo, carboxy, hydroxy, keto, A2-lower alkoxy, A2-guanido, benzyl or cyclohexylmethyl. Also, if the mono or bicyclic heterocycloalky ring has an available N atom such N atom can also be substituted by an N-protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, benzyl or benzhydryl.
The term xe2x80x9chaloxe2x80x9d refers to chloro, bromo, fluoro and iodo.
The terms xe2x80x9calkylenexe2x80x9d and xe2x80x9csubstitued alkylenexe2x80x9d refer to a bridge of 1 to 10 carbons such as xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)9xe2x80x94, etc. One or more hydrogens, preferably one, in the alkylene bridge can be replaced by an alkyl, substituted alkyl, carboxy, alkoxycarbonyl, amino, xe2x80x94NH(lower alkyl), xe2x80x94N(lower alkyl)2, hydroxy, aminocarbonyl, alkoxycarbonylamino, halo, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, hetereoaryl, or heterocycloalkyl, e.g. 
The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9csubstituted alkenylxe2x80x9d refer to a bridge of 2 to 10 carbons having one or more double bonds, preferably 2 to 6 carbons with one double bond, such as xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, etc. One or more hydrogens, preferably one, in the alkenyl bridge can be replaced by an alkyl, substituted alkyl, carboxy, alkoxycarbonyl, amino, xe2x80x94NH(lower alkyl), xe2x80x94N(lower alkyl)2, hydroxy, aminocarbonyl, alkoxycarbonylamino, halo, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or heterocycloalkyl, e.g. 
The term xe2x80x9calkynylxe2x80x9d and xe2x80x9csubstituted alkynylxe2x80x9d refer to a bridge of 2 to 10 carbons having one or more triple bonds, preferably 2 to 6 carbons with one triple bond, such as xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, etc. One or more hydrogens in the alkynyl bridge can be replaced by an alkyl, substituted alkyl, carboxy, alkoxycarbonyl, amino, carboxy, alkoxycarbonyl, amino, xe2x80x94NH(lower alkyl), xe2x80x94N(lower alkyl)2, hydroxy, aminocarbonyl, alkoxycarbonylamino, halo, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or heterocycloalkyl, e.g. 
The compounds of formulas IV, V and VI can be prepared as follows.
The carboxy substituted azetidinone of the formula: 
wherein P3 is a silyl protecting group such as tert-butyldimethylsilyl is treated with an alkyldihalide of the formula:
Clxe2x80x94(CH2)qxe2x80x94Ixe2x80x83xe2x80x83(VIII)
in the presence of base to give the carboxy substituted azetidinone of the formula: 
The carboxy substituted azetidinone of formula IX is then treated with an azide such as sodium azide followed by a fluoride ion salt such as tetrabutylammonium fluoride to remove the silyl group and give 
Hydrogenation of the compound of formula X by treating with hydrogen in the presence of palladium on carbon catalyst gives the alkylamino compound of the formula: 
The alkylamino compound of formula XI, preferably as an acid salt, is reacted with the diprotected guanylating agent of the formula: 
wherein P1 is an N-protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl and L is a leaving group such as methylthio or pyrazolyl to give the azetidinone compound of the formula: 
Coupling the intermediate of compound XIII with an amine selected from 
gives the compound of the formula: 
Reacting the intermediate of formula XIV with a chloro compound selected from 
reacting with OCNxe2x80x94SO2xe2x80x94R9 gives the compound of the formula: 
Removal of the N-protecting groups gives the compounds of formulas IV, V and VI.
The compounds of formula IV and VI wherein R1 or R14 is carboxy or alkoxy carbonyl can be prepared by reacting the intermediate of formula XIII with an alcohol, bromide, or iodide of the formula:
HOxe2x80x94Z, Brxe2x80x94Z, or Ixe2x80x94Zxe2x80x83xe2x80x83(XVI)
wherein Z is alkyl, substituted alkyl, benzyl or benzhydryl. When XVI is HOxe2x80x94Z, the reaction is performed in the presence of a coupling reagent such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylamino)propyl carbodiimide, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, or carbonyldiimidazole. When XVI is Brxe2x80x94Z or Ixe2x80x94Z, the reaction is performed in the presence of a base such as sodium carbonate or bicarbonate. The reaction gives the compound of the formula: 
Reacting the intermediate of formula XVII with a chloro compound selected from 
reacting with OCNxe2x80x94SO2xe2x80x94R7 gives the compound of the formula: 
When Z is a protecting group such as benzyl or benzhydryl, removal of this group and the N-protecting groups from the compound of formula XVIII gives the desired compounds of formulas IV and VI wherein R1 or R14 is carboxy.
Also, when Z is alkyl or substituted alkyl and X1 is 
the compound of formula XVIII can be treated to remove the N-protectings groups followed by mild aqueous hydrolysis to give the desired compounds of formula IV and VI wherein R1 or R14 is carboxy.
In the above procedures when X1 is a group such as 
etc., the intermediate of formula XIV or XVII can be reacted with a carbamoyl chloride 
wherein Prot is an N-protecting group such as tert-butoxycarbonyl followed by removal of the N-protecting group and coupling with an acid such as 
etc, in the presence of a coupling reagent.
The compounds of formula III can be prepared by treating the carboxy substituted azetidinone of formula IX with a haloalkyl of the formula:
xe2x80x83haloxe2x80x94R12xe2x80x83xe2x80x83(XIX)
in the presence of base wherein halo is Cl, Br, or I to give the azetidinone 
The azetidinone of formula XX can also be prepared by reacting the azetidinone of formula VII with the haloalkyl of formula XIX in the presence of base to give the azetidinone of the formula: 
Treatment of the compound of formula XXI with an alkyldihalide of formula VIII in the presence of base gives the azetidinone of formula XX.
The azetidinone of formula XX is then reacted in the same manner as the azetidinone of formula IX described above to give the desired compounds of formula III.
The compounds of formula II wherein R1 is other than alkyl can be prepared by treating the olefin of the formula: 
with chlorosulfonylisocyanate to give the azetidinone of the formula: 
Oxidation of compound XXIII such by treatment with, for example, potassium permanganate followed by silylation with a tri(lower alkyl) silyl chloride gives the azetidinone of the formula: 
The azetidinone of formula XXIV is then reacted in the same manner as the azetidinone of formula VII described above to give the desired compounds of formula II.
The compounds of formula II wherein R11 and R1 are both alkyl can be prepared by treating the azetidinone of the formula: 
wherein R1and R11, are both alkyl in the same manner as the azetidinone of formula VII described above. The dialkyl substituted azetidinones of formula XXV are known in the art, for example, see U.S. Pat. No. 4,775,670.
The compounds of formula IV and VI wherein R1or R14 is xe2x80x94(CH2)2-aryl can be prepared by reacting an N-protected guanidine of the formula: 
with an N-protected compound of the formula:
xe2x80x83P2xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90CH-arylxe2x80x83xe2x80x83(XXVII)
wherein P2 is trimethylsilyl in the presence of lithium diisopropylamide to give the azetidinone of the formula: 
The azetidinone of formula XXVIII is then reacted with a chloro compound selected from 
or Clxe2x80x94SO2xe2x80x94R7, or with OCNxe2x80x94SO2xe2x80x94R7 to give, following the reduction of the alkene group and removal of the P1 protecting groups, the desired compounds of formulas IV and VI.
Compounds of formula II, IV, and VI can also be prepared by reacting the chloro compound of the formula: 
with the N-protected compound of the formula: 
in the presence of base to give the azetidinone of the formula: 
Treatment of the azetidinone of formula XXXI with an azide such as sodium azide gives the azetidinone 
Treatment of the compound of formula XXXII with ceric ammonium nitrate removes the methoxyphenyl group and the resulting azetidinone can be reacted in the same manner as the azetidinone of formula X described above to give the desired compounds of formulas II, IV, and VI.
The compounds of formula I where A1 is 
can be prepared by reacting the compound of the formula: 
wherein L1 is a leaving group such as bromo or iodo with the azetidinone of formula VII, XXI, XXIV or XXV in the presence of base to give the azetidinone of the formula: 
Removal of the P1 protecting group and treatment of this azetidinone as 10 described above for the azetidinone of formula XI gives the desired compounds of formula I. Alternatively, the azetidinone of formula XXXIV can first be treated with a chloro compound to introduce the desired X1 group, deprotected, and then reacted with the guanylating agent of formula XII.
Alternatively, the compounds of formula I wherein A1 is 
R1 is xe2x80x94(CH2)2-aryl and R2 and R3 are hydrogen can be prepared by reacting a compound of the formula: 
with the reagent of formula XXVII in the presence of lithium diisopropylamine to give the azetidinone of the formula: 
Removal of the P1 protecting group and reaction with the guanylating agent compound of formula XII gives the azetidinone of the formula: 
Reacting the intermediate of formula XXXVII with a chloro compound selected from 
or CLxe2x80x94SO2xe2x80x94R7, or reacting with OCNxe2x80x94SO2xe2x80x94R7 followed by reduction of the alkene group and removal of the P1 protecting groups gives the desired compounds of formula I.
As discussed above, when X1 is a group such as 
etc., the intermediate azetidinone can be reacted with a carbamoyl chloride 
wherein Prot is as defined above followed by removal of the N-protecting group and coupling with an acid such as 
etc, in the presence of a coupling reagent to introduce the desired X1 moiety.
Alternatively, the compounds of formula I wherein A1 is 
can be prepared from the azetidinone of formula XXXVII. According to this process, the ring nitrogen is protected by treating the azetidinone of formula XXXVII with, for example, tert-butyldimethylsilyl chloride. Treating with ozone reduces the moiety 
to an aldehyde which is then converted to a carboxylic acid by Jones oxidation or by treating with sodium chlorite and sulfamic acid. Removal of the silyl protecting group gives the azetidinone of the formula: 
Treatment of this azetidinone as described above for the azetidinone of formula XIII gives the desired compounds of formula I.
The following is a preferred route to the intermediate of formula XIII. According to this procedure, the silyl protected azetidinone of formula VII is treated with the N-protected iodo compound of the formula: 
to give after removal of the silyl protecting group the azetidinone of the formula: 
which may be isolated as an amine salt such as the tert-butylamine salt.
The P1 protecting groups are removed from the azetidinone of formula XL and the resulting compound is reacted with the diprotected guanylating agent of formula XII to give the intermediate of formula XIII which again may be isolated as an amine salt such as the tert-butylamine salt.
The iodo compound of formula XXXIX can be prepared by reacting the diprotected amine of the formula: 
with the alkyldihalide of formula VIII to give the chloro compound of the formula: 
The chloro compound of formula XLII is then treated with sodium iodide in the presence of base to give the iodo compound of formula XXXIX.
The following alternate procedure can also be employed to prepare the compounds of formulas IV and VI.
The azetidinone of formula IX is reacted with benzylchloroformate in the presence of triethylamine and dimethylaminopyridine to give the benzyl ester of the formula: 
Treatment of the chloro compound of formula XLIII with sodium iodide gives the iodo compound of the formula: 
The iodo compound of formula XLIV is reacted with the diprotected guanidine of the formula: 
to give the azetidinone compound of the formula: 
Removal of the silyl protecting group P3 from the azetidinone of formula XLVI for example by reacting with ammonium fluoride gives the azetidinone compound of the formula: 
Reacting the intermediate of formula XLVII with a chloro compound 
or Clxe2x80x94SO2xe2x80x94R7, or reacting with OCNxe2x80x94SO2xe2x80x94R7 gives the compound of the formula: 
Removal of the benzyl protecting group and the P1 N-protecting groups from the azetidinone of formula XLVIII gives the desired compounds of formulas IV and VI.
The compounds of formula I wherein A1 is 
can be prepared by reacting the azetidinone of formula XL with an alcohol, bromide, or iodide of formula XVI to give the azetidinone of the formula: 
Reacting the intermediate of formula XLIX with a chloro compound selected from 
reacting with OCNxe2x80x94SO2xe2x80x94R9 gives the compound of the formula: 
Removal of the P1 protecting groups such as by treatment with trifluoroacetic acid when P1 is tert-butoxycarbonyl gives the trifluoroacetic acid amine salt of the formula: 
Treatment of the trifluoroacetic acid amine salt of formula LI with the appropriate aldehyde in the presence of a reducing agent such as triacetoxy borohydride or sodium cyanoborohydride gives the compound of the formula: 
The compound of formula LII is reacted with the diprotected guanylating agent of formula XII to give the azetidinone of the formula: 
Removal of the P1 and Z protecting groups gives the desired compounds of formula I.
The azetidinone compounds of formula I to VI and various intermediates and starting materials employed in their synthesis contain one or two asymmetric carbons as denoted below at ring positions 3 and 4
Of course, the compounds of formula II where R1 and R11 are the same and the compounds of formula VI where R14 is hydrogen contain only one asymmetric ring carbon. Additional asymmetric carbons may be present in the compounds of formula I to VI depending upon the definitions of the substituents R1, A1, X1, X2, R13, X3 and R14. As is well known in the art, see for example J. March. Advanced Organic Chemistry, Fourth Edition, John Wiley and Sons, New York, N.Y. (1991), pages 94-164, such asymmetric carbon atoms give rise to enantiomers and diastereomers, and all such stereoisomers, either in pure form or in the form of mixtures, are included within the scope of this invention. In addition, when alkenes are present in the compounds of formula I to VI, they may, when appropriately substituted exist as cis or trans isomers, or as mixtures thereof. Again, all such forms are within the scope of this invention.
The compounds of formula I to VI can be obtained as a pharmaceutically acceptable salt, as a physiologically hydrolyzable ester, or as a solvate. The compounds of formulas I to IV and VI wherein R1 or R14 is carboxy can exist in the form of an inner salt or zwitterion. All such forms are within the scope of this invention. Pharmaceutically acceptable salts include salts with mineral acids such as hydrochloric, hydrobromic, phosphoric and sulfuric as well as salts with organic carboxylic acids or sulfonic acids such as acetic, trifluoroacetic, citric, maleic, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic, malic, methanesulfonic, p-toluensulfonic and the like. Preparation of these acid addition salts is carried out by conventional techniques.
The novel compounds of formulas I to V and the compounds of formula VI possess tryptase inhibition activity. This activity was confirmed using either isolated human skin tryptase or recombinant human tryptase; prepared from the human recombinant beta-protryptase expressed by baculovirus in insect cells. The expressed beta-protryptase was purified using sequential immobilized heparin affinity resin followed by an immunoaffinity column using an anti-tryptase monoclonoal antibody. The protryptase was activated by auto-catalytic removal of the N-terminal in the presence of dextran sulfate followed by dipeptidyl peptidase I (DPPI) removal of the two N-terminal amino acids to give the mature active enzyme (Sakai et al., J. Clin. Ivest., 97, pages 988-995, 1996). Essentially equivalent results were obtained using isolated native enzyme or the activated expressed enzyme. The tryptase enzyme was maintained in 2M sodium chloride, 10 nM 4-morpholinepropanesulfonic acid, pH 6.8.
The assay procedure employed a 96 well microplate. To each well of the microplate (Nunc MaxiSorp), 250 xcexcl of assay buffer [containing low molecular weight heparin and tris (hydroxymethyl)aminomethane] was added followed by 2.0 xcexcl of the test compound in dimethylsulfoxide. The substrate (10 xcexcl) was then added to each well to give a final concentration of either 370 xcexcM benzoyl-arginine-p-nitroaniline (BAPNA) or 100 xcexcM benzyloxycarbonyl-glycine-proline-arginine-p-nitroaniline (CBz-Gly-Pro-Arg-pNA). Similar data was obtained using either substrate. The microplate was then shaken on a platform vortex mixer at a setting of 800 (Sarstedt TPM-2). After a total of three minutes incubation, 10 xcexcl of the working stock solution of tryptase (6.1 mM final tryptase concentration for use with BAPNA or 0.74 nM for use with CBz-Gly-Pro-Arg-pNA) was added to each well. The microplate was vortexed again for one minute and then incubated without shaking at room temperature for an additional 2 minutes. After this time the microplate was read on a microplate reader (Molecular Devices UV max) in the kinetic mode (405 nm wavelength) over twenty minutes at room temperature. To determine the compound concentration that inhibited half of the enzyme activity (IC50), the fraction of control activity (FCA) was plotted as a function of the inhibitor concentration (I) and curve to fit FCA/(1+[I]/IC50). The IC50 for each compound was determined 2-4 times and the obtained values were averaged.
As a result of this tryptase activity, the compounds of formula I to VI as well as an inner salt thereof, a pharmaceutically acceptable salt thereof, a hydrolyzable ester thereof, or a solvate thereof, are useful as antiinflammatory agents particularly in the treatment of chronic asthma and may also be useful in treating or preventing allergic rhinitis, inflammatory bowel disease, psoriasis, conjunctivitis, atopic dermatitis, rheumatoid arthritis, osteoarthritis, and other chronic inflammatory joint diseases, or diseases of joint cartilage destruction. Additionally, these compounds may be useful in treating or preventing myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture. Additionally, these compounds may be useful for treating or preventing diabetic retinopathy, tumor growth and other consequences of angiogenosis. Additionally, these compounds may be useful for treating or preventing fibrotic conditions, for example, fibrosis, scleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas and hypertrophic scars.
The compounds of formula I to VI are also inhibitors of Factor Xa and/or Factor VIIa. As a result, the compounds of formula I to VI as well as an inner salt or a pharmaceutically acceptable salt thereof, a hydrolyzable ester thereof, or a solvate thereof may also be useful in the treatment or prevention of thrombotic events associated with coronary artery and cerebrovascular disease which include the formation and/or rupture of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes, ischemia and angina (stable and unstable), deep vein thrombosis (DVT), disseminated intravascular coagulopathy, Kasacach-Merritt syndrome, pulmonary embolism, myocardial infarction, cerebral infarction, cerebral thrombosis,transient ischemic attacks, atriala fibrillation, cerebral embolism, thromboembolic complications of surgery (such as hip or knee replacement, introduction of artificial heart valves and endarterectomy) and peripheral arterial occulsion and may also be useful in treating or preventing myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture. The compounds of formula I to VI possessing Factor Xa and/or Factor VIIa inhibtion activity may also be useful as inhibitors of blood coagulation such as during the preparation, storage and fractionation of whole blood.
The compounds of formula I to VI are also inhibitors of urokinase-type plasminogen activator. As a result, the compounds of formula I to VI as well as an inner salt or a pharmaceutically acceptable salt thereof, a hydrolyzable ester thereof, or a solvate thereof may be useful in the treatment or prevention of restenosis and aneurysms, in the treatment or prevention of myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture, and may also be useful in the treatment of malignancies, prevention of metastases, prevention of prothrombotic complications of cancer, and as an adjunct to chemotherapy.
The compounds of formulas I to V also possess thrombin and trypsin inhibitory activity similar to that reported by Han in the U.S. patents noted previously for the compounds of formula VI. As a result, the compounds of formula I to V as well as an inner salt or a pharmaceutically acceptable salt thereof, a hydrolyzable ester thereof, or a solvate thereof may be useful in treating or preventing pancreatitis, in the treatment or prevention of thrombotic events associated with coronary artery and cerebrovascular disease as described above, and may also be useful as inhibitors of blood coagulation such as during the preparation, storage, and fractionation of whole blood.
Certain compounds of formulas I to IV are also useful due to their selective tryptase inhibition activity. These compounds while having potent tryptase inhibition activity are much less active against other enzyme systems including trypsin, thrombin and Factor Xa. For example, this selective tryptase activity is seen with the compounds of formulas I to IV where X1 or X2 is the group 
and R25 is a spacer terminating in a lipophilic group. Suitable spacers include groups of 3 or more atoms such as 
etc., as well as groups containing 2 or more atoms and a phenyl, substituted phenyl, cycloalkyl, heteroaryl, or heterocycloalkyl ring such as 
etc. Suitable lipophilic terminal groups include aryl, substituted aryl, cycloalkyl, heteroaryl, heterocycloalkyl, etc. These compounds of formulas I to IV as well as an inner salt, a pharmaceutically acceptable salt thereof, a hydrolyzable ester thereof, or a solvate thereof, are useful as antiinflammatory agents particularly in the treatment of chronic asthma and may also be useful in treating or preventing allergic rhinitis as well as some of the other diseases described above for the non-selective tryptase inhibitors. It is believed that as a result of their selective tryptase inhibition activity that these compounds will have less tendency to produce unwanted side-effects.
The compounds of formula I to VI as well as an inner salt or a pharmaceutically acceptable salt thereof, a hydrolyzable ester thereof, or a solvate thereof may be administered orally, topically, rectally or parenterally or may be administered by inhalation into the bronchioles or nasal passages. The method of administration will, or course, vary upon the type of disease being treated. The amount of active compound administered will also vary according to the method of administration and the disease being treated. An effective amount will be within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg per day in a single or multiple doses administered at appropriate intervals throughout the day.
The composition used in these therapies can be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms such as tablets, pills, powders, liquid solutions or suspensions, liposomes, injectable and infusible solutions. Such compositions can include pharmaceutically acceptable carriers, preservatives, stabilizers, and other agents conventionally employed in the pharmaceutical industry.
When the compounds of formula I to VI as well as an inner salt or a pharmaceutically acceptable salt thereof, a hydrolyzable ester thereof, or a solvate thereof are employed to treat asthma or allergic rhinitis they will preferably be formulated as aerosols. The term xe2x80x9caerosolxe2x80x9d includes any gas-borne suspended phase of the active compound which is capable of being inhaled into the bronchioles or nasal passage. Aerosol formulations include a gas-borne suspension of droplets of the active compound as produced in a metered dose inhaler or nebulizer or in a mist sprayer. Aerosol formulations also include a dry powder composition suspended in air or other carrier gas. The solutions of the active compounds of formulas I to VI used to make the aerosol formulation will be in a concentration of from about 0.1 to about 100 mg/ml, more preferably 0.1 to about 30 mg/ml, and most preferably from about 1 to about 10 mg/ml. The solution will usually include a pharmaceutically acceptable buffer such as a phosphate or bicarbonate to give a pH of from about 5 to 9, preferably 6.5 to 7.8, and more preferably 7.0 to 7.6. Preservatives and other agents can be included according to conventional pharmaceutical practice.
Other pharmaceutically active agents can be employed in combination with the compounds of formula I to VI depending upon the disease being treated. For example, in the treatment of asthma, xcex2-adrenergic agonists such as albuterol, terbutaline, formoterol, fenoterol or prenaline can be included as can anticholinergics such as ipratropium bromide, anti-inflammatory cortiocosteroids such as beclomethasone, triamcinolone, flurisolide or dexamethasone, and anti-inflammatory agents such as cromolyn and nedocromil.
In addition to the novel compounds of formulas I to V and the methods of use for the compounds of formulas I to VI, this invention is also directed to novel intermediates and novel synthetic routes employed in the preparation of such compounds.
Preferred compounds of this invention are those of formula IV wherein:
q is 3;
R1 is carboxy, 
xe2x80x83R6 is aminocarbonyl, 
xe2x80x83R4 in the definition of Y and X2 is alkyl, cycloalkyl, substituted alkyl, substituted cycloalkyl, xe2x80x94(CH2)1 to 6-aryl, or heteroaryl;
R7 is alkyl, cycloalkyl, substituted alkyl, substituted cycloalkyl, xe2x80x94(CH2)0 to 4-aryl, xe2x80x94(CH2)0 to 4-aryl-A3-aryl, xe2x80x94(CH2)0 to 4-heteroaryl, xe2x80x94(CH2)0 to 4-heterocycloalkyl, xe2x80x94(CH2)0 to 4-heteroaryl-A3-aryl, 
xe2x80x83is amino, xe2x80x94NH(alkyl) xe2x80x94N(alkyl)2 or xe2x80x94NHxe2x80x94(CH2)1 to 4-aryl;
R9 is lower alkyl;
A3 is a bond, an alkylene bridge of 1 to 6 carbons, 
xe2x80x83d and e are independently selected from zero and an integer from 1 to 6 provided that the sum of d plus e is no greater than 10;
R21 and R22 are independently selected from hydrogen and lower alkyl; and an inner salt or pharmaceutically acceptable salt thereof.
Also preferred are the compounds of this invention of formula I wherein 
R2 and R3 are both hydrogen;
R1 is a defined above; 
xe2x80x83wherein Y, R4 and R9 are as preferably defined above;
t is two or three;
u is one; and an inner salt or a pharmaceutically acceptable salt thereof.
Most preferred are the following compounds of formula IV including an inner salt or a pharmaceutically acceptable salt thereof: 
Also most preferred are the following compounds of formula I as diastereomeric mixtures including an inner salt or pharmaceutically acceptable salt thereof: 
and the individual homochiral compounds especially: 
The following compounds of formula IV including an inner salt or a pharmaceutically acceptable salt thereof are also preferred: 
The following compounds of formula I including an inner salt or a pharmaceutically acceptable salt thereof are also preferred: 